The objectives of the proposed research are 1) to develop a better understanding of the clinical variability and genetics of von Willebrand's disease (vWd) in order to improve the diagnosis and treatment of this disorder and 2) to investigate the potential role of "von Willebrand factor(s)" in the pathogenesis of thrombosis. Preliminary studies have documented significant variability in measurable abnormalities in patients with vWd including qualitative abnormalities of factor VIII-related antigen. Although true variants of vWd may exist, it is clear that further longitudinal studies are required to define the spectrum of this disorder. The specific aims of the research are: (1) to perform serial studies of 50-60 individuals in 15-20 different families with clinical vWd to determine the degree of variability within individual subjects, between individuals in a family, between affected families and in normal subjects. The variable factors to be studied will include the bleeding time, factor VIII activity, factor VIII-related antigen (quantitative and qualitative) and Ristocetin co-factor, (2) to define the asymptomatic carrier state of vWd and determine the incidence of phenotypically normal carriers (detected by abnomalities of fVIIIRA and Rcof) by performing a survey of at least 200 normal individuals, (3) to determine the degree and duration of changes in the above factors following transfusion of plasma or cryoprecipitate in subjects with vWd who require treatment, (4) to study the effect of standardized, maximum exercise on the above factors in selected subjects with vWd and in normal volunteers, in order to evaluate the degree of dissociation of these factors in response to stress, (5) to obtain preliminary studies of the possible role of factors associated with vWd in the thrombotic complications of disorders known to be associated with elevated levels of factor VIII (sickle cell anemia and diabetes).